Capsaicin receptor subtypes in pain transduction

描述(申请人提供)：疼痛，最古老的医学问题之一，仍然是一个巨大的临床挑战。我们有效治疗急性、尤其是慢性疼痛疾病的能力往往会导致其他有害的副作用，从而降低生活质量。TRPV1，也被称为辣椒素受体，一直处于研究的前沿，专注于开发治疗炎症引起的慢性疼痛的新策略。TRPV1在检测疼痛刺激的初级传入伤害性感受器(专门的感觉神经元)中表达，在炎症条件下，其表达在这些神经细胞中增加。TRPV1水平的升高似乎推动了持续性疼痛和痛觉过敏的发展。令人惊讶的是，在正常或炎症条件下，是什么控制了神经系统中TRPV1的产生，人们知之甚少。目前的项目主要集中在：1)了解损伤部位释放的炎症介质，如神经生长因子(NGF)如何在炎症条件下增加TRPV1的产生。我们最近证实，NGF对大鼠TRPV1基因的转录控制区具有正向调节作用。基于更多的数据，我们现在建议研究Sp1样转录因子家族与NGF/炎症介导的TRPV1依赖性疼痛增加之间的联系。2)另一个研究领域是通过与其他TRPV1剪接变异体的共表达来调节TRPV1的表达活性。以前，我们发现了一个TRPV1剪接变异体(VR.5‘SV)，当它在体外共表达时，可以阻断TRPV1对伤害性刺激的激活。我们现在建议研究VR.5‘SV和其他TRPV1剪接变体在单个感觉神经元中的生理后果。通过研究伤害性神经元的个体反应特性，并将这些反应与剪接变异体表达的分子特征进行匹配，我们将确定TRPV1剪接变异体在控制伤害性感受器激活和疼痛转导中的作用。与公共卫生相关：炎症性疾病引起的慢性疼痛的基础尚不清楚。探测辛辣辣椒灼烧感的受体对于维持感觉神经的炎症性疼痛是重要的。我们正在研究一种减少或关闭感觉神经中这种受体的产生的方法，作为控制慢性外周炎症引起的疼痛的一种方法。

DESCRIPTION (provided by applicant): Pain, one of the oldest medical problems still remains an immense clinical challenge. Our ability to effectively treat acute and especially chronic painful conditions often causes other unwanted side-effects that degrade the quality of life. TRPV1, also known as the capsaicin receptor, has been at the forefront of research focused on the development of new strategies to treat chronic painful conditions that arise from inflammation. TRPV1 is expressed in primary afferent nociceptors (specialized sensory neurons) that detect painful stimuli and its expression is increased in these nerve cells under conditions of inflammation. Increased levels of TRPV1 appear to drive the development of persistent pain and hyperalgesia. Surprisingly, little is known about what controls the production of TRPV1 in the nervous system under normal or inflammatory conditions. The current project is focused on: 1) Understanding how inflammatory mediators released at the site of injury, such as Nerve Growth Factor (NGF), increase TRPV1 production under conditions of inflammation. We have recently demonstrated that NGF positively regulates the transcriptional control regions in the rat TRPV1 gene. Based on additional data, we now propose to study a link between the Sp1- like family of transcription factors and NGF / inflammation mediated increases in TRPV1 dependent pain. 2) Another area of study is the regulation of TRPV1 expressed activity through its co-expression with other TRPV1 splice variants. Previously, we identified a TRPV1 splice variant (VR.5'sv) that when co-expressed, blocks TRPV1 activation to noxious stimuli in vitro. We now propose to study the physiologic consequence of VR.5'sv and other TRPV1 splice variants in individual sensory neurons. By studying the individual response properties of nociceptive neurons and matching these responses to a molecular signature of splice variant expression, we will determine the role of TRPV1 splice variants in the control of nociceptor activation and pain transduction. PUBLIC HEALTH RELEVANCE: The basis for chronic pain arising from inflammatory conditions is poorly understood. The receptor that detects the burning sensation to pungent hot chili peppers is important for maintaining inflammatory pain in sensory nerves. We are studying a way to reduce or turn off the production of this receptor in sensory nerves as a way to control the pain from chronic peripheral inflammation.